Amyloidosis is not a single disease entity but rather a diverse group of progressive disease processes characterized by extracellular tissue deposits of a waxy, starch-like protein called amyloid, which accumulates in one or more organs or body systems. As the amyloid deposits accumulate, they begin to interfere with the normal function of the organ or body system. There are at least fifteen different types of amyloidosis. The major forms are primary amyloidosis without known antecedent, secondary amyloidosis following some other condition, and hereditary amyloidosis.
Secondary amyloidosis occurs during chronic infection or inflammatory disease, such as tuberculosis, a bacterial infection called familial Mediterranean fever, bone infections (osteomyelitis), rheumatoid arthritis, inflammation of the small intestine (granulomatous ileitis), Hodgkin's disease, and leprosy.
Amyloid deposits include amyloid P (pentagonal) component (AP), a glycoprotein related to normal serum amyloid P (SAP), and sulphated glycosaminoglycans (GAG), complex carbohydrates of connective tissue. Amyloid protein fibrils, which account for about 90% of the amyloid material, comprise one of several different types of proteins. These proteins are capable of folding into so-called “beta-pleated” sheet fibrils, a unique protein configuration which exhibits binding sites for Congo red resulting in the unique staining properties of the amyloid protein.
Many diseases of aging are based on or associated with amyloid-like proteins and are characterized, in part, by the buildup of extracellular deposits of amyloid or amyloid-like material that contribute to the pathogenesis, as well as the progression of the disease. These diseases include, but are not limited to, neurological disorders such as Alzheimer's Disease (AD), Lewy body dementia, Down's syndrome, hereditary cerebral hemorrhage with amyloidosis (Dutch type); the Guam Parkinson-Dementia complex. Other diseases which are based on or associated with amyloid-like proteins are progressive supranuclear palsy, multiple sclerosis; Creutzfeld Jacob disease, Parkinson's disease, HIV-related dementia, ALS (amyotropic lateral sclerosis), Adult Onset Diabetes; senile cardiac amyloidosis; endocrine tumors, and others, including ocular disorders such as macular degeneration.
Although pathogenesis of these diseases may be diverse, their characteristic deposits often contain many shared molecular constituents. To a significant degree, this may be attributable to the local activation of pro-inflammatory pathways thereby leading to the concurrent deposition of activated complement components, acute phase reactants, immune modulators, and other inflammatory mediators (McGeer et al., 1994).
Alzheimer's Disease (AD) is a neurological disorder primarily thought to be caused by amyloid plaques, an accumulation of abnormal deposit of proteins in the brain. The most frequent type of amyloid found in the brain of affected individuals is composed primarily of Aβ fibrils. Scientific evidence demonstrates that an increase in the production and accumulation of beta-amyloid protein in plaques leads to nerve cell death, which contributes to the development and progression of AD. Loss of nerve cells in strategic brain areas, in turn, causes reduction in the neurotransmitters and impairment of memory. The proteins principally responsible for the plaque build up include amyloid precursor protein (APP) and two presenilins (presenilin I and presenilin II). Sequential cleavage of the amyloid precursor protein (APP), which is constitutively expressed and catabolized in most cells by the enzymes β and γ secretase, leads to the release of a 39 to 43 amino acid Aβ peptide. The degradation of APPs likely increases their propensity to aggregate in plaques. It is especially the Aβ(1-42) fragment that has a high propensity of building aggregates due to two very hydrophobic amino acid residues at its C-terminus. The Aβ(1-42) fragment is therefore believed to be mainly involved in, and responsible for, the initiation of neuritic plaque formation in AD and to have, therefore, a high pathological potential.
There is therefore a need for therapeutic agents that prevent the formation of amyloid plaques and/or diffuse existing plaques in patients with AD. In particular what is needed are agents capable of counteracting the physiological manifestations of the disease such as the formation of plaques associated with aggregation of fibers of the amyloid or amyloid-like peptide.
Passive immunization against beta-amyloid has become an increasingly desirable strategy as a therapeutic treatment for AD. The effectiveness of passive immunization has been demonstrated in transgenic animal models of AD, where anti-Ab therapies have been shown to reduce plaque burden and reverse behavioral deficits. In spite of overcoming hyper-activation of cytotoxic T-cells, a risk of active immunization with Ab, passive immunization still carries the risk of Fg receptor-mediated over-activation of microglia cells and complement activation, which may contribute to an inappropriate pro-inflammatory response and vasogenic edema.
Anti-amyloid beta antibodies have been described, for example, in WO 2007/068412 published Jun. 21, 2007; WO 2008/060364 published May 22, 2008; WO 2007/068412 published Jun. 21, 2007; WO 2007/068412 published Jun. 21, 2007; WO 2007/068412 published Jun. 21, 2007; WO 2007/068412 published Jun. 21, 2007; WO 2008/156621 published Dec. 24, 2008; WO 2008/156621 published Dec. 24, 2008; WO 2008/156621 published Dec. 24, 2008 (see also Table 2).
Side effects observed during treatment of patients having amyloidosis such as AD with anti-beta amyloid antibodies include inflammatory side effects, such as meningitis and meningoencephalitis, and fluid build up in the brain (cerebral edema). Therapies that reduce or eliminate the complications associated with an amyloidosis are needed.